Intractable Epilepsy due to MTR Deficiency: Importance of Homocysteine Analysis
16 January 2017
16 May 2017
30 June 2017 (eFirst)
Background Methionine synthase deficiency is a rare inborn error of intracellular cobalamin metabolism caused by mutations in the MTR (5-methyltetrahydrofolate-homocysteine S-methyltransferase) gene, resulting in megaloblastic anemia and neurologic symptoms.
Methods and Results We describe for the first time a homozygous MTR gene c.3518C > T (p.P1173L) mutation in a patient with severe megaloblastic anemia, developmental delay, and drug-resistant seizures associated with hyperhomocysteinemia and hypomethioninemia. Methionine synthase activity was only 9% of the reference value, and MTR protein expression was decreased in the fibroblasts of the patient. The clinical features of our patient are similar to previously published patients with the complementation type G disorder of methionine synthase deficiency with the exception of drug-resistant seizures. However, intramuscular injections of hydroxocobalamin (OHCbl) in conjunction with betaine and folic acid provided verified clinical and electrophysiological treatment response.
Conclusion This study emphasizes the importance of early diagnosis of patients having neurologic symptoms due to methionine synthase deficiency where early treatment has significant effects on the clinical outcome of the patients. Elevated level of plasma homocysteine together with low methionine in plasma amino acid analysis should raise a suspicion of remethylation disorder.
Keywordsdrug-resistant epilepsy - methionine synthase deficiency - cblG - MTR gene - plasma homocysteine
This work was supported by grants from the Research Council for Health of the Academy of Finland (JU, Decision number 138566; RH, Decision number 266498 and 273790), the Foundation for Pediatric Research, Special State Grants for Health Research in the Department of Pediatrics and Adolescence at Oulu University Hospital, Oulu, Finland, The Alma and K. A. Snellman Foundation, Oulu, Finland, and Finnish Cultural Foundation, North Ostrobothnia Regional Fund.
- 1 Watkins D, Rosenblatt DS. Functional methionine synthase deficiency (cblE and cblG): clinical and biochemical heterogeneity. Am J Med Genet 1989; 34 (03) 427-434
- 2 Watkins D, Ru M, Hwang HY. , et al. Hyperhomocysteinemia due to methionine synthase deficiency, cblG: structure of the MTR gene, genotype diversity, and recognition of a common mutation, P1173L. Am J Hum Genet 2002; 71 (01) 143-153
- 3 Harding CO, Arnold G, Barness LA, Wolff JA, Rosenblatt DS. Functional methionine synthase deficiency due to cblG disorder: a report of two patients and a review. Am J Med Genet 1997; 71 (04) 384-390
- 4 Carmel R, Watkins D, Goodman SI, Rosenblatt DS. Hereditary defect of cobalamin metabolism (cblG mutation) presenting as a neurologic disorder in adulthood. N Engl J Med 1988; 318 (26) 1738-1741
- 5 Rosenblatt DS, Thomas IT, Watkins D, Cooper BA, Erbe RW. Vitamin B12 responsive homocystinuria and megaloblastic anemia: heterogeneity in methylcobalamin deficiency. Am J Med Genet 1987; 26 (02) 377-383
- 6 Wilson A, Leclerc D, Saberi F. , et al. Functionally null mutations in patients with the cblG-variant form of methionine synthase deficiency. Am J Hum Genet 1998; 63 (02) 409-414
- 7 Schiff M, Benoist JF, Tilea B, Royer N, Giraudier S, Ogier de Baulny H. Isolated remethylation disorders: do our treatments benefit patients?. J Inherit Metab Dis 2011; 34 (01) 137-145
- 8 Huemer M, Bürer C, Ješina P. , et al. Clinical onset and course, response to treatment and outcome in 24 patients with the cblE or cblG remethylation defect complemented by genetic and in vitro enzyme study data. J Inherit Metab Dis 2015; 38 (05) 957-967
- 9 Leclerc D, Campeau E, Goyette P. , et al. Human methionine synthase: cDNA cloning and identification of mutations in patients of the cblG complementation group of folate/cobalamin disorders. Hum Mol Genet 1996; 5 (12) 1867-1874
- 10 Alazami AM, Patel N, Shamseldin HE. , et al. Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families. Cell Reports 2015; 10 (02) 148-161
- 11 Poloschek CM, Fowler B, Unsold R, Lorenz B. Disturbed visual system function in methionine synthase deficiency. Graefes Arch Clin Exp Ophthalmol 2005; 243 (05) 497-500